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Dissecting the Roles and Requirements for RBM39 in Acute Myeloid Leukemia and Normal Hematopoiesis

Award Number: K08CA245242
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Dissecting the Roles and Requirements for RBM39 in Acute Myeloid Leukemia and Normal Hematopoiesis - PROJECT SUMMARY/ABSTRACT Research: RNA binding proteins (RBPs) regulate diverse cellular processes including transcription, translation, and regulation of gene expression, and are frequently dysregulated in cancers. Through an unbiased genetic screen aimed at identifying cancer-specific RBP dependencies, we recently identified a specific requirement for RBM39 in malignant myeloid cancers and that cancers bearing RNA splicing factor mutations as being particularly sensitive to the anti-cancer sulfonamides. RBM39 is an RBP that functions in RNA splicing and recently, a class of clinical-grade “anti-cancer sulfonamide” compounds were demonstrated to degrade RBM39 protein by co-opting the Ddb1/CUL4 ubiquitin-ligase complex as their mechanism of action. Thus, the primary goal of this project is to assess differential and tissue-specific requirements for RBM39 in normal hematopoiesis versus myeloid malignancies, and to assess requirements for RBM39 for leukemia initiation and maintenance. This proposal will utilize a novel conditional knockout (cKO) mouse for Rbm39 and several associated newly developed in vitro and in vivo murine models to pursue this goal. We expect these investigations to further our understanding of the role of RBM39 in normal physiology and cancer as well as provide new therapeutic insights into the on- and off-target toxicities of the anti-cancer sulfonamides. These goals are particularly timely given that several of these molecules have already proven excellent safety in multiple phase I/II trials and are now ripe for therapeutic testing in a patient population most likely to benefit from RBM39 degradation. Candidate: Dr. Sydney X. Lu is a graduating hematology & medical oncology fellow in the Department of Medicine at MSKCC. He aims to become an independent, tenure- track physician-scientist investigating the molecular pathogenesis of hematological malignancies through a combination of genetics, functional genomics, and murine modeling. Dr.Lu has outlined a five-year period of mentored training to strengthen his skills in functional genomics and disease modeling. This training period will be carried out under the mentorship of Dr. Omar Abdel-Wahab, a leader in the functional genomics of hematopoietic malignancies. Dr. Lu has also assembled an advisory committee composed of Drs. Ross Levine, Martin Tallman, Michael Kharas, and Christine Mayr who will help guide his training and research. Environment: MSKCC is the world's oldest and largest private cancer center, devoting more than 130 years to exceptional patient care, innovative research, and outstanding educational programs. MSKCC exposes trainees to an exceptionally robust academic research environment with a strong commitment and track record of successfully supporting junior faculty who are seeking careers as independent physician-scientists.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	5	11/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $241,634 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	5	6/4/2024	NON-COMPETING CONTINUATION	$241,634
														Subtotal = $241,634

Issue Date FY: 2023 ( Subtotal = $241,634 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	002	4	6/19/2023	NON-COMPETING CONTINUATION	$241,634
2023	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	3	1/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$81,495
2023	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	2	1/30/2023	NON-COMPETING CONTINUATION	-$81,495
														Subtotal = $241,634

Issue Date FY: 2022 ( Subtotal = $241,634 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	3	8/19/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$241,634
2022	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	2	8/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $241,634

Issue Date FY: 2021 ( Subtotal = $241,634 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	2	7/9/2021	NON-COMPETING CONTINUATION	$241,634
														Subtotal = $241,634

Issue Date FY: 2020 ( Subtotal = $241,634 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	1	2/6/2020	NEW	$241,634
														Subtotal = $241,634

Grand Total All Awards = $1,208,170

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Dissecting the Roles and Requirements for RBM39 in Acute Myeloid Leukemia and Normal Hematopoiesis

Award Number: K08CA245242

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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